Cerebrovascular Senescence Is Associated With Tau Pathology in Alzheimer's Disease.
Cerebrovascular Senescence Is Associated With Tau Pathology in Alzheimer's Disease.
复制标题
DOI：
10.3389/fneur.2020.575953
复制
发表时间：
2020
影响因子：
3.4
通讯作者：
Bennett RE
中科院分区：
文献类型：
--
作者：
Bryant AG;Hu M;Carlyle BC;Arnold SE;Frosch MP;Das S;Hyman BT;Bennett RE
阿尔茨海默病（AD）与神经病理改变有关，包括tau神经原纤维缠结（nft）和淀粉样斑块的聚集。越来越多的证据表明，血管功能障碍在AD的发病和进展中也起着关键作用，部分是通过内皮功能障碍。基于tau病理诱导血管异常和细胞衰老的动物模型发现，我们假设人类AD大脑中的tau病理导致血管衰老。为了探索这一假设，我们从16名Braak晚期（Braak V/VI, B3）和12名对照（Braak 0/I/II, B1）受试者的背外侧前额叶皮层（PFC, BA9）分离了完整的微血管，并量化了42个与衰老、细胞粘附和各种内皮细胞功能相关的基因的表达。在调整性别和脑血管病理后，B3微血管中与内皮衰老和白细胞粘附相关的基因，包括SERPINE1 （PAI-1）、CXCL8 （il - 8）、CXCL1、CXCL2、ICAM-2和TIE1显著上调。特别是，在调整性别、脑血管病理和死亡年龄后，B3微血管中与衰老相关的分泌表型基因SERPINE1和CXCL8上调了2倍以上。13名受试者（n = 9 B3, n = 4 B1）纵向血浆样本的蛋白质定量数据显示，血浆衰老或黏附相关蛋白水平无显著差异，表明这些变化与全身血管改变无关。未来对外周和皮层血管中衰老生物标志物的研究可以进一步阐明人类AD中tau病理与血管变化之间的联系。
Alzheimer's Disease (AD) is associated with neuropathological changes, including aggregation of tau neurofibrillary tangles (NFTs) and amyloid-beta plaques. Mounting evidence indicates that vascular dysfunction also plays a key role in the pathogenesis and progression of AD, in part through endothelial dysfunction. Based on findings in animal models that tau pathology induces vascular abnormalities and cellular senescence, we hypothesized that tau pathology in the human AD brain leads to vascular senescence. To explore this hypothesis, we isolated intact microvessels from the dorsolateral prefrontal cortex (PFC, BA9) from 16 subjects with advanced Braak stages (Braak V/VI, B3) and 12 control subjects (Braak 0/I/II, B1), and quantified expression of 42 genes associated with senescence, cell adhesion, and various endothelial cell functions. Genes associated with endothelial senescence and leukocyte adhesion, including SERPINE1 (PAI-1), CXCL8 (IL8), CXCL1, CXCL2, ICAM-2, and TIE1, were significantly upregulated in B3 microvessels after adjusting for sex and cerebrovascular pathology. In particular, the senescence-associated secretory phenotype genes SERPINE1 and CXCL8 were upregulated by more than 2-fold in B3 microvessels after adjusting for sex, cerebrovascular pathology, and age at death. Protein quantification data from longitudinal plasma samples for a subset of 13 (n = 9 B3, n = 4 B1) subjects showed no significant differences in plasma senescence or adhesion-associated protein levels, suggesting that these changes were not associated with systemic vascular alterations. Future investigations of senescence biomarkers in both the peripheral and cortical vasculature could further elucidate links between tau pathology and vascular changes in human AD.
登录
查看更多内容
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
11
作者：
BULLOCK, R;MAXWELL, WL;ADAMS, JH
通讯作者：
ADAMS, JH
影响因子：
3.7
作者：
Cho, Sun-Jung;Yun, Sang-Moon;Koh, Young Ho
通讯作者：
Koh, Young Ho
影响因子：
3.3
作者：
Bussière, T;Gold, G;Hof, PR
通讯作者：
Hof, PR
影响因子：
5.9
作者：
Benedictus MR;Leeuwis AE;Binnewijzend MA;Kuijer JP;Scheltens P;Barkhof F;van der Flier WM;Prins ND
通讯作者：
Prins ND